JP2876144B2 - 3-Phenylcoumarin-7-yloxyacetic acid derivatives and their preparation and use - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel 3-phenylcoumarin-7-yloxyacetic acid derivative or a salt thereof useful as a pharmaceutical.

[Conventional technology]

With the westernization of dietary habits, the number of diabetic patients has increased sharply in recent years, and treatment for them is urgently needed. Conventionally, insulin and hypoglycemic agents have been widely used as antidiabetic drugs.However, since diabetes is a disease accompanied by various complications as well as mere abnormal glucose metabolism, the above drugs alone are not sufficient. .

BACKGROUND ART As a cause of various complications in diabetes such as retinopathy, cataract, neuropathy, and nephropathy, accumulation of intracellular sorbitol via a polyol pathway, which is a glucose metabolic pathway, has attracted attention. The enzyme that catalyzes the conversion between aldose and polyol, which is the first step in the polyol pathway, is called aldose reductase, and this enzyme is considered to be the rate-limiting enzyme in the polyol pathway. By inhibiting this aldose reductase and reducing the production and accumulation of sorbitol, it is possible to prevent or treat diabetic complications as described above [RG Jurjylmish et al .: New England
Journal of Medicine (New Eng. J. Med.), 308
Vol. 119-125 (1983): JH Kinoshita et al .: Metabolism, 28 (1), 462-469 (1979)] [Problems to be Solved by the Invention] The objects of the present invention are as described above. An object of the present invention is to provide an agent useful for inhibiting a novel aldose reductase.

[Means for solving the problem]

The present invention provides a compound of the general formula (I) (Wherein, R ¹ , R ² , R ³ and R ¹ ′, R ² ′, R ³ ′, R ⁴ ′, R ⁵ ′ represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group). ) Or a salt thereof, which is an aldose reductase inhibitor containing these as an active ingredient. The compound of the present invention can be produced as follows.

That is, the general formula (II) (Where R ¹ , R ² , R ³ and R ¹ ′, R ² ′, R ³ ′, R ⁴ ′, R ⁵ ′ have the same meanings as in the above general formula (I)). The resulting 7-hydroxy-3-phenylcoumarin derivative is reacted with a halogenoacetic acid ester and then hydrolyzed. In this specification, the term "lower" means that the group to which this term is attached has 6 or less, preferably 4 or less carbon atoms.

The compound of the general formula (II) as a raw material of the compound of the present invention is obtained by a Perkin-Oglialoro reaction from a substituted β-resorsilaldehyde and a substituted phenylacetic acid as shown in the following reaction formula (a). Can be synthesized (NRKrishnas-wamy, et.al., Indian.
J. Chem., 4, 120. (1966). Reaction formula (a) Synthesis of the compound of the general formula (I) by reacting the compound of the general formula (II) with a halogen acetate is carried out by a usual method. For example, an ester of the compound of the general formula (I) is obtained by reacting with potassium carbonate and ethyl bromoacetate in acetone.

Hydrolyzing the obtained ester of the compound of the general formula (I) with water or a mineral acid in acetic acid, or hydrolyzing with a basic acid,
By adjusting the pH to about 4 with a mineral acid, the acid becomes a free acid, that is, an acid of the compound of the formula (I), and this is converted to an acid with an inorganic base at pH 9
By adjusting the distance to the vicinity, an inorganic salt of the compound of the general formula (I) can be obtained.

All of these can be isolated by a known method, for example, concentration, drying and other methods, and purified by recrystallization. The mineral acids used here include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like, and the inorganic bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide and the like. And alkali carbonates such as alkali hydroxide, sodium carbonate, potassium carbonate and ammonium carbonate, and alkali bicarbonates such as sodium bicarbonate, potassium bicarbonate and ammonium bicarbonate.

The aldose reductase inhibitor containing the compound represented by the general formula (I) or a salt thereof as an active ingredient can be used in the form of tablets, capsules, injections, powders, pills, granules using a commonly used carrier according to a conventional method. It may be used for preparations, suppositories, eye drops, etc.

〔Example〕

Next, the compound of the present invention, its production method and aldose reductase inhibitory action will be described in detail with reference to examples, but the present invention is not limited to the following examples. The melting points of the products in each of the examples are not corrected.

Reference Example 1 5.0 g (0.036 mol) of β-resorsilaldehyde and 5.6 g (0.036 mol) of sodium phenylacetate were added to 30 m of acetic anhydride.
and heat to reflux for 9 hours. After cooling, water is added, and the precipitated crystals are collected and dried. Then, after recrystallization from ethanol / acetone, 3.0 g of the obtained 7-acetyl-3-phenylcoumarin is added to a mixture of 40 ml of acetic acid and 10 ml of concentrated hydrochloric acid, and the mixture is heated under reflux for 2 hours. After the reaction, the mixture flows into ice water, and the precipitated crystals are collected. After drying and recrystallizing with acetone / benzene, 7-
2.1 g of hydroxy-3-phenylcoumarin are obtained. Compound 1 in [Table 1], yield 77.7%, mp 209-210 ° C.

Reference Example 2 Compounds 2 to 12 in Table 1 are obtained in the same manner as in Reference Example 1. Table 1 shows the physical property values of the general formula (II) thus obtained.

Example 1 2.0 g of 7-hydroxy-3-phenylcoumarin (0.008
Mol), 1.4 g (0.008 mol) of ethyl bromoacetate, 0.1 g of potassium iodide and 10 g of anhydrous potassium carbonate in 50 ml of acetone
The mixture is heated under reflux for 4 hours with stirring. After cooling, the insolubles are separated, and the residue obtained by evaporating the solvent is dissolved in ether. The ether solution is washed with water, a 50% by weight aqueous sodium hydroxide solution and water in this order, and the ether layer is dried over anhydrous sodium sulfate. The solvent is distilled off, and the obtained residue is recrystallized from acetone / hexane to obtain 1.95 g (yield: 71.6%) of ethyl 3-phenylcoumarin-7-yloxyacetate.

1.95 g of the above ester is added to a mixture of 30 ml of ethanol and 15 ml of a 5% by weight aqueous sodium hydroxide solution, and the mixture is refluxed for 30 minutes. After cooling, the insolubles are separated and the solution is acidified with hydrochloric acid. The precipitated crystals are collected. After drying and recrystallization with acetone, 3-phenylcoumarin-7-yloxyacetic acid 1.
45 g are obtained. 80.0% yield, mp 212-214 ° C, [Table 2]
Compound 1 in.

Example 2 In the same manner as in Example 1, compounds 2 to 12 in Table 2 are obtained. Table 2 shows the physical property values of the derivatives of the compound of the formula (I) thus obtained. The aldose reductase inhibitory activity of formula (I) compounds are shown in Table 2 at IC _50.

<Aldose reductase inhibitory action> A 7-week-old male Wistar rat was sacrificed under ether anesthesia, and the lens was immediately removed.

Lens is 1.0mM 2-mercaptoethanol and 1.0mM
NADP (oxidized nicotinamide adenine dinucleotide ph
osphate) and homogenized with 100 mM sodium-potassium-phosphate buffer (pH 6.8). Then 12,000r
After centrifugation at pm for 15 minutes, the supernatant was used as a sample for aldose reductase activity measurement. All the above operations were performed at 4 ° C, and the samples were stored at -80 ° C.

Aldose reductase activity is measured by KADOR
The method was carried out according to the method described in Biophysical Chemistry 8 (1978) 81-85. That is, 0.1 mM NAD as coenzyme
PH (reduced nicotinamide adenine dinucleotide phosph
ate) and 100 mM sodium-potassium-phosphate buffer containing 2.0 mM DL-glyceraldehyde as substrate (pH 6.
2) To 970μ, 10μ of various concentrations of the compound of the present invention were added, and then 20μ of the above-mentioned sample was added, and the reaction was carried out at 25 ° C. Using a control lacking only the substrate, the decrease in absorbance at 340 nm was measured for 200 seconds. In addition, instead of adding the sample solution, only the solvent was added, and the reaction was performed in the same manner as described above. The absorbance was measured using UV-260 (manufactured by Shimadzu Corporation). As a result, as shown in Table 2, the inhibitory activity against aldose reductase was 0.18 to 5.5 (1 × 1) at 50% inhibition.
0 ^-7 M).

<Acute toxicity> When an acute toxicity test of the compound of general formula (I) obtained in each of the above examples by oral administration was performed using ddy mice (body weight 23 to 25 g), even the oral administration of 2 g / kg resulted in death. No cases were found.

〔The invention's effect〕

As is clear from the above results, the novel 3-phenylcoumarin-7-yloxyacetic acid derivative of the present invention has an aldose reductase inhibitory activity and is useful as a highly safe therapeutic drug for diabetic complications.

Following (72) inventor Toyama, Toyama Prefecture Kamifugo 92 address Megumi Terajima (72) inventor Suzui Akio Amagasaki, Hyogo Prefecture Miyauchi-cho 2-chome address 42 of the front page (58) investigated the field (Int.Cl. ^6, DB name) C07D 311/00-311/74 REGISTRY (STN) CA (STN)

Claims (3)

(57) [Claims] 1. The compound of the general formula (I) (Where R ¹ , R ² , R ³ and R ¹ ′, R ² ′, R ³ ′, R ⁴ ′, R ⁵ ′ represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group) A 3-phenylcoumarin-7-yloxyacetic acid derivative represented by the formula: or a salt thereof. 2. A compound of the general formula (II) (Where R ¹ , R ² , R ³ and R ¹ ′, R ² ′, R ³ ′, R ⁴ ′, R ⁵ ′ have the same meanings as in the above general formula (I)) Reacting a 7-hydroxy-3-phenylcoumarin derivative with a halogenoacetic acid ester and then hydrolyzing the derivative;
A method for producing a phenylcoumarin-7-yloxyacetic acid derivative or a salt thereof. 3. An aldose reductase inhibitor comprising a 3-phenylcoumarin-7-yloxyacetic acid derivative represented by the above general formula (I) or a salt thereof as an active ingredient.